Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPΒ

T. L. Gustafson, E. Wellberg, B. Laffin, L. Schilling, R. P. Metz, C. A. Zahnow, W. W. Porter

Research output: Contribution to journalArticle

Abstract

We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cells has not been determined. In this study, we show that transformation of MCF10A cells by Harvey-Ras (Ha-Ras) induces CCAAT/enhance binding protein Β (C/EBPΒ) and activates the NOTCH signaling pathway to block SIM2s gene expression. NOTCH-mediated repression acts through a C-repeat binding factor 1 (CBF1)-independent mechanism, as introduction of CBF1 had no effect on SIM2s expression. Consistent with C/ebpΒ-dependent inhibition of SIM2s, C/ebpΒ / mouse mammary glands express high levels of SIM2s and reestablishment of C/ebpΒ isoforms decreased SIM2s mRNA levels in C/ebpΒ immortalized mammary epithelial cell lines. These studies illustrate a novel pathway of tumor suppressor gene silencing in Ha-Ras-transformed breast epithelial cells and identify SIM2s as a target of C/EBPΒ and NOTCH signaling.

Original languageEnglish (US)
Pages (from-to)1561-1568
Number of pages8
JournalOncogene
Volume28
Issue number12
DOIs
StatePublished - Mar 26 2009

Keywords

  • C/EBP-beta
  • Mammary gland
  • NOTCH
  • Singleminded-2s

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Gustafson, T. L., Wellberg, E., Laffin, B., Schilling, L., Metz, R. P., Zahnow, C. A., & Porter, W. W. (2009). Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPΒ. Oncogene, 28(12), 1561-1568. https://doi.org/10.1038/onc.2008.497